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EP3013343B1 - Composition pharmaceutique antivirale active - Google Patents

Composition pharmaceutique antivirale active Download PDF

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Publication number
EP3013343B1
EP3013343B1 EP14733198.7A EP14733198A EP3013343B1 EP 3013343 B1 EP3013343 B1 EP 3013343B1 EP 14733198 A EP14733198 A EP 14733198A EP 3013343 B1 EP3013343 B1 EP 3013343B1
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EP
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Prior art keywords
pharmaceutical composition
test
atropine
viral infection
virus
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Active
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EP14733198.7A
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German (de)
English (en)
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EP3013343A1 (fr
Inventor
Sigurd Puetter
Richard Ammer
Michael Schmidbauer
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Medice Arzneimittel Puetter & Co KG GmbH
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Medice Arzneimittel Puetter & Co KG GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/28—Mercury; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising atropine or a salt thereof; Aconite and mercury cyanide for use in a method of treating a viral infection.
  • Viruses are the main cause of colds. Among them rhinoviruses and coronaviruses, which account for 50-70% of all respiratory infections, occupy the top spots, followed by parainfluenza viruses, RSV, adeno- and enteroviruses. Influenza, another acute respiratory disease, is also caused by viruses. On top of that, herpes simplex viruses (HSV) benefit from the concomitant immune deficiency and may, under certain circumstances, cause corresponding symptoms such as herpes labialis.
  • HSV herpes simplex viruses
  • Phytotherapeutics and complex homeopathic remedies can be such an alternative.
  • such alternatives have been and continue to be discussed because they have advantages in terms of greater therapeutic index, better tolerability, and fewer drug interactions than synthetic remedies, as well as the risk of resistance formation.
  • the complex homeopathic medicine Meditonsin® consists of the herbal components atropine and aconitine as well as the salt mercury cyanide (Mercurius cyanatus) and has been used for over 60 years for the treatment of inflammation of the throat, nose and throat. Clinical studies confirm efficacy in the treatment of upper respiratory tract inflammation and good tolerability.
  • EP 0 513 878 discloses a solution containing, inter alia, cetylpyridinium chloride at 0.10 g, atropine hydrochloride at 0.004 g, and mercuric cyanide at 0.004 g (based on 100 ml). Antiviral activity of the solution against influenza viruses is described, more specifically, mercury II cyanide and cetylpyridinium chloride.
  • US 2011/105423 relates to compounds that modulate the replication of RNA viruses such as influenza viruses.
  • RNA viruses such as influenza viruses.
  • An example of such compounds is, inter alia, called aconitine.
  • US2002031509 refers to a pharmaceutical composition comprising an antimicrobially effective amount of at least one snake venom. Also described is a composition which further contains a plant extract, for example aconitin.
  • the present patent application thus relates to the surprising finding that a pharmaceutical composition comprising atropine or a salt thereof, aconitin and mercury cyanide can be advantageously used for the treatment of viral infections.
  • the present invention shows the antiviral properties of a mixture of the active ingredients atropine, aconitin and mercury cyanide in various concentration ranges. It could be shown that the mixture inhibited the activity of all tested viruses strongly to very strongly.
  • the present invention thus relates to a pharmaceutical composition comprising atropine or a salt thereof, aconitin and mercury cyanide for use in a method of treating a viral infection, wherein the viral infection is caused by herpesviruses, rhinoviruses, RSV (human respiratory syncytial virus) and / or Enterovirus is caused.
  • the viral infection is caused by herpesviruses, rhinoviruses, RSV (human respiratory syncytial virus) and / or Enterovirus is caused.
  • FIG. 1 the antiviral activity of the pharmaceutical composition according to the invention is given as a function of the concentration, measured as relative inhibition in percent.
  • the associated individual values can be found in Table 3.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting essentially of a) atropine or a salt thereof; b) aconitine; and c) mercury cyanide for use in a method of treating a viral infection, wherein the viral infection is caused by herpesviruses, rhinoviruses, RSV (human respiratory syncytial virus) and / or enteroviruses.
  • the viral infection is caused by HRV14 (human rhinovirus type 14), HSV1 (herpes simplex virus type 1), and / or CA9 (human coxsackie virus type 9).
  • HRV14 human rhinovirus type 14
  • HSV1 herpes simplex virus type 1
  • CA9 human coxsackie virus type 9
  • composition includes in particular peroral dosage forms, for example, solid, semi-liquid or liquid compositions for oral administration.
  • An aqueous / ethanolic solution for dropwise administration has been found to be particularly advantageous.
  • mixtures of ethanol 94% (w / w), glycerol 85% and purified water in the weight ratio 5:10:85 are used particularly advantageously.
  • dosage forms are possible, for example, solid peroral forms such as powders, tablets or capsules.
  • the preparation is carried out in particular according to the rules for the production of homeopathic medicines according to the Homeopathic Pharmacopoeia 2012 (HAB 2012), official edition.
  • HAB 2012 Homeopathic Pharmacopoeia 2012
  • tablets can be pressed from the appropriate triturations.
  • limited additions of magnesium stearate or calcium behenate can be used as a lubricant and of starch as a disintegrant.
  • aqueous lactose solution, ethanol and suitable concentrations of starch pastes may be used.
  • globules can be prepared according to the HAB 10 rule, wherein sugar globules are uniformly moistened with 1/100 mass parts of the dilution in question and dried in air.
  • the pharmaceutical composition of the present invention may include parenterals, ie liquid dilutions for injection as well as liquid rubs and ointments, suppositories, eye drops, nasal drops prepared in accordance with HAB Rules 11-15 and 45.
  • the present pharmaceutical composition is a peroral solution prepared according to the regulations of the Homeopathic Pharmacopoeia.
  • phrases "consists essentially of” means that the pharmaceutical composition contains these ingredients as effective ingredients. However, it may further contain one or more solvents, adjuvants, etc., which, while necessary for the preparation of a pharmaceutical composition, do not or do not significantly contribute to the pharmacological activity.
  • Atropine is a tropane alkaloid which is a racemic of the isomeric (R) - and (S) -hyoscyamine according to the following structural formula.
  • the (R) -form is given above, the (S) -form below:
  • Atropine belongs to the parasympatholytics and competes with the muscarinic receptors of the parasympathetic nervous system with the neurotransmitter acetylcholine.
  • the physical effects of taking atropine are as follows: acceleration of the heart rate, dilation of the bronchi, decreased salivation, etc.
  • other, but rare, applications have been described, for example, the use in spasms of the gastrointestinal tract, Difficult bladder emptying and urinary incontinence.
  • use as an antiviral agent has not previously been described.
  • the salt of atropine used according to the invention is usually atropine sulfate, for example atropine sulfate monohydrate.
  • Atropine or its salt is used at a concentration of 1 to 100 ⁇ g / ml, preferably 1 to 10 ⁇ g / ml, more preferably 2 to 7 ⁇ g / ml, and most preferably 3.13 to 6.25 ⁇ g / ml , According to the invention, it has been found that if atropine sulfate is used in combination with the other ingredients of the pharmaceutical composition, a lower dosage of atropine sulfate is to be expected (see below). In other words, at a lower concentration, an at least comparable, possibly even significantly better anti-viral effect can be achieved.
  • Aconitin is used as a further component of the pharmaceutical composition.
  • Aconitin is a diterpenoid alkanoid that slows down the inactivation of the voltage-gated sodium channel, thereby prolonging the influx of sodium ions during the action potential of the nerves. In this respect, it acts first of all centrally and peripherally on the motor and sensory nerves, first excitably followed by paralysis. Cardiac effects may include arrhythmias, bradycardia and diastolic cardiac arrest.
  • the dose lethalis of Aconitin is approximately 5 mg in adults.
  • Aconitin has the following structural formula:
  • Aconitin is used as an effective ingredient of the composition according to the invention in a concentration between 0.05-100 ⁇ g / ml, for example, 0.5-100 ⁇ g / ml, preferably 0.05-5 ⁇ g / ml, more preferably 0.5-2 ⁇ g / ml, and most preferably 0.16-1.56 ⁇ g / ml aconitine.
  • a synergistic effect can be achieved, ie an over-additive antiviral effect at the same or lower dosage of the individual components.
  • the third component of the pharmaceutical composition of the invention is mercuric cyanide (Hg (CN) 2).
  • Mercury cyanide is a highly toxic compound used only in homeopathy for the treatment of diphtheria, severe angina and colds.
  • Mercury cyanide is used as the component of the composition of the invention in concentrations between 0.001 to 10 ⁇ g / ml, preferably 0.001 to 0.1 ⁇ g / ml, more preferably 0.001 to 0.01 ⁇ g / ml, most preferably 0.003 to 0.006 ⁇ g / ml of mercury cyanide in solution ,
  • the pharmaceutical composition of the present invention comprises a combination of atropine (or a salt thereof), especially atropine sulfate, and aconitine and mercury cyanide.
  • atropine or a salt thereof
  • atropine sulfate especially atropine sulfate
  • aconitine and mercury cyanide for such a composition, it has proven to be advantageous to set the concentration of the respective individual constituents lower than in the case of the particular individual substance.
  • the pharmaceutical composition according to the invention for example in the form of an aqueous / ethanolic solution, may contain about 1-10, preferably 5 ⁇ g / ml of atropine sulfate, about 0.5-5, preferably 1 ⁇ g / ml of aconitin and about 0.001-0.1 ⁇ g / ml, preferably 0.004 ⁇ g / ml, of mercury cyanide.
  • An advantageous composition according to the present invention comprises a total concentration of about 3-9 ⁇ g / ml of the aforementioned ingredients. How out FIG. 1 As can be seen, the best results with regard to the antiviral activity are found at a total concentration of 6 ⁇ g / ml, but even with lower values, for example a total concentration of 3 ⁇ g / ml, outstanding inhibition values were still achieved.
  • a particularly preferred composition comprises a solution of ethanol, glycerol and water containing approximately 5 ⁇ g / ml of atropine sulfate, 1 ⁇ g / ml of aconitine and 0.004 ⁇ g / ml of mercury cyanide.
  • Such a composition is already known, as described in the introduction, and is successfully under the name "Meditonsin®" for decades on the European market.
  • the use of the triple combination over the antiviral activity of the individual components has a synergistic effect.
  • the so-called “meditonsin” mixture is particularly active against RSV, CA9, HRV14 and HSV1 strongly to very strongly antivirally. This in particular taking into account the fact that the concentrations of the individual components used in the mixture are lower than the amounts used in each case for the individual experiments.
  • Table 2 shows a comparative illustration of the antiviral activity between the substances atropine sulfate, aconitine and mercury cyanide and their mixture.
  • the percentage plaque inhibition is stated as the measurement result.
  • the percentage of plaque inhibition for the mixture of 5 ⁇ g / ml atropine sulfate, 1 ⁇ g / ml aconitine and 0.004 ⁇ g / ml mercury cyanide based on HSV1 is 69.53%.
  • the inhibitory effect of the mixture on HSV1 is almost twice as high.
  • a plaque inhibition of almost 70% is an excellent value, which illustrates the high therapeutic potential of the mixture used.
  • the pharmaceutical composition of the present invention (mixture) is administered to the adult patient in a total daily dose of about 20 ⁇ g / ml atropine sulfate, 4 ⁇ g / ml aconitine and 0.016 ⁇ g / ml mercury cyanide. Deviations of approx. ⁇ 30% from the stated quantity are tolerable.
  • the composition having the concentrations indicated above.
  • the dosage is halved for children between 6 and 12 years of age, is further reduced for infants from the age of 1 and is about 25% for infants from the age of 7 months.
  • the purpose of the antiviral testing described below was to investigate the antiviral effects of atropine sulfate, aconitine and mercury cyanide and a mixture of these three substances.
  • the antiviral testing of atropine sulfate, aconitine and mercury cyanide and a mixture of these three substances is divided into two phases.
  • a cytotoxicity test of the test substances is carried out in various dilution stages in order to find out from which dilution stage no cytotoxic effect is exerted by the test substances on the virus carrier, non-virus-infected cell lines.
  • the antiviral activity of the test substances in different dilution stages is examined for the viruses used in the test, starting with the test substance dilution, from which no cytotoxic effect is exerted on the cell lines.
  • test samples for the toxicity test and the subsequent test for antiviral activity were prepared according to the following table.
  • Atropine sulfate (AT) 100 mg / 10 ml / 80% ethanol 10 mg / ml / 80% ethanol 1 mg / ml / 8% ethanol No.
  • AC 0.01 mg in 1 ml / 0.008% ethanol
  • QC 0.00004 mg in 4 ml / 0.000043% ethanol
  • the cytotoxicity of the test samples was examined by means of the MTT test (metabolic test).
  • the MTT test metabolic performance testing assays were performed in 96-well microtiter plates for microscopic analysis in 24-well microtiter plates.
  • the determination of the metabolic performance in the MTT test is carried out by the quantitative analysis of the mitochondrial enzyme activity.
  • the colorimetric test according to Mosmann is based on the conversion of the colorless MTT salt (dimethylthiazole-diphenylterazolium bromide) into blue, water-insoluble formazan crystals by mitochondrial dehydrogenases. In this case, a direct correlation between the vitality or the metabolic activity and the enzyme activity of the cells can be measured.
  • the toxicity test was carried out. All test solutions were followed by further log2 or log10 dilution gradings. All test substance dilutions were added in parallel to growing BGM, HEp-2 and HeLa cells. Thereafter, the treated cell cultures were incubated for a total of 3 days and 5 days, respectively, at 37 ° C and 5% CO 2 . As controls, cells were carried with medium alone (untreated control) or with 8, 4, 2, 1 and 0.004% ethanol in the medium (ethanol control).
  • the analysis in the MTT test was carried out on day 1 and day 3 or on day 1 and day 5 after substance addition.
  • the treated cells were incubated with the MTT solution for a further 2 to 4 hours and, after solubilization of the formazan crystals in dimethylsulfoxide (DMSO), the optical density (OD) of the cell culture supernatants in the photometer was determined at 570 nm (RF690nm).
  • DMSO dimethylsulfoxide
  • RF690nm optical density
  • the microscopic evaluation of an altered cell morphology was carried out on day 3 or day 5 after substance addition on the criterion of an unchanged cell morphology or on enlarged cells with vacuolization to a detached cell lawn.
  • the OD values of the untreated controls were defined as 100% vitality.
  • the OD values of the test batches were reported as percentages (% toxicity). It was possible to determine the 50% inhibitory dose (IC 50 ) in dose-response curves of the respective test samples over several parallel samples up to the concentration, which had no test substance-related impairment for use in the antiviral tests.
  • the quantitative analysis of the antiviral activity was carried out in plaque reduction assays and in virus-specific enzyme immunoassays.
  • MOI multiplicity of infection
  • the virus plaques can be visualized as bright courts in the dark colored cell lawn.
  • the determination of the plaque number was carried out with the aid of an image processing system.
  • plaque count of the untreated control was defined as 100% infection.
  • plaque counts of the respective test mixtures were evaluated so that inhibitory effects of the substances to be analyzed could be shown as percent inhibition of substance (% inhibition).
  • Enzyme immunoassay (ELISA) (analysis of virus production)
  • the micro test strips are coated with antibodies against the specific viruses.
  • the viruses present in the cell culture supernatant of the infected cell lines bind to the solid phase-fixed antibodies.
  • the enzyme peroxidase-labeled pathogen-specific detection antibodies that are directed against the corresponding viruses. If the substrate / chromogen and also hydrogen peroxide and tetramethylbenzidine are added in a further step, an enzyme-substrate-chromogen reaction results in a blue dye.
  • the intensity of the staining is determined photometrically (extinction) in the photometer at a wavelength of 450 nm (OD450); it is proportional to the viral antigen content.
  • the analysis of virus production in infected and treated cells was carried out by the determination of viral proteins (conserved virus-specific antigens in RSV) in the ELISA.
  • viral proteins conserved virus-specific antigens in RSV
  • the confluent-grown virus-sensitive cells cell turf
  • MOI defined Virus solution
  • virus inoculum was withdrawn and the infected cell lawn washed. This was followed by the addition of the physiological substance concentrations.
  • the respective test mixtures were cultured until microscopically a 70% to go-percent CPE was observed in the untreated virus controls.
  • the newly synthesized viruses were in the cell culture supernatant at this stage. This was followed by the decrease of the virus-containing cell culture supernatants for the analysis of the viral proteins in the ELISA.
  • extinction values (OD492nm) of the untreated controls determined in the ELISA after the enzyme reactions were defined as 100% infection.
  • OD of the respective test mixtures was evaluated so that inhibitory effects of the substances to be analyzed could be shown as percent inhibition of substance (% inhibition).
  • the virus-infected cells were treated immediately after infection with the test substances.
  • the virus-sensitive cells were infected with the respective prepared virus solutions (HEp-2: RSV, HSV1, BGM: CA9, HeLa: HRV14).
  • the respective viral infections were with a mean infection dose (M.O.I. multiplicity of infection) of 0.0004 (RSV, HSV1, HRV14) and 0.0003 (CA9), respectively.
  • test solutions in different dilution stages were carried out after checking for possible intoxication in the cell vitality tests.
  • the dilution series began with non-cytotoxic concentrations of 50 ⁇ g / ml (test specimen No.1 and No.2), 2 ⁇ g / ml (test specimen No.3) and 6 ⁇ g / ml (test specimen No.4).
  • the dilution was carried out in log2 or log10 increments.
  • Table 1 shows the concentrations of the test samples used in the antiviral test.
  • the quantitative analysis of an antiviral activity was carried out in the plaque reduction assay by counting the virus plaques on day 3 to day 5 according to the test batch using an image processing system.
  • the cell culture supernatants of the infected and treated cells were tested for the content of newly synthesized viral proteins in enzyme immunoassays (ELISA).
  • Antiviral agents were used to verify the test system, ribavirin (Viracole®) for RSV, acyclovir (Zovirax®) for HSV1 and oxymetazoline hydrochloride (OMZ) for HRV14.
  • ribavirin (Viracole®) for RSV
  • acyclovir (Zovirax®) for HSV1
  • oxymetazoline hydrochloride (OMZ) for HRV14.
  • M.O.I. oxymetazoline hydrochloride
  • Table 2 Comparative presentation of the antiviral activity between the substances atropine sulfate, aconitine and mercury cyanide and their mixture. Here the percentage of plaque inhibition is given as measurement results. The measurement results of the individual substances are given for the concentration range corresponding to that which was present in the mixture.
  • Table 2 shows the values for antiviral activity as measured by the percent inhibition of viral activity, atropine sulfate, aconitine and mercury cyanide and the mixture of these three substances. For the individual substances, only those measured values are given, which were measured in the concentration ranges which corresponded to those of the individual substances in the mixture. The following substance concentrations were present in the mixture: 5 ⁇ g / ml atropine sulfate, 1 ⁇ g / ml aconitin and 0.004 ⁇ g / ml mercury cyanide.
  • Table 2 clearly shows, first, that the overall effect of the mixture is higher than the effect of the substances as individual and, secondly, that the antiviral activity of the mixture is not due to an addition of the antiviral activity of the individual substances but to a synergistic effect. For example, if there was an additive effect in the case of antiviral effect on HSV1 the readings of the mixture are between 22.69 and 51.73, which is not the case. In fact, the mixture shows a value of 69.53.
  • Table 3 In vitro test of the antiviral activity of pharmaceutical composition as a function of the concentration, measured as relative inhibition in percent (see FIG.

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Claims (7)

  1. Composition pharmaceutique comprenant :
    a) l'atropine ou un de ses sels ;
    b) l'aconitine ; et
    c) le cyanure de mercure ;
    destinée à l'emploi dans un procédé de traitement d'une infection virale, l'infection virale étant due à des virus de l'herpès, à des rhinovirus, au RSV (virus respiratoire syncytal humain) et/ou à des entérovirus.
  2. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon la revendication 1, l'infection virale étant due au HRV14 (rhinovirus de type 14 humain), au HSV1 (virus de l'herpès simplex de type 1), et/ou du CA9 (virus Coxsackie de type 9 humain).
  3. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon une ou plusieurs des revendications précédentes, la composition se présentant sous la forme d'une solution aqueuse éthanolique et contenant environ 5 µg/ml de sulfate d'atropine, environ 1 µg/ml d'aconitine et environ 0,004 µg/ml de cyanure de mercure.
  4. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon la revendication 1 ou 2, la composition contenant entre 1 et 10 µg/ml, préférentiellement de 2 à 7 µg/ml, le préférentiellement de 3,13 à 6,25 µg/ml de sulfate d'atropine.
  5. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon une ou plusieurs des revendications 1 à 2, la composition contenant entre 0,05 et 5 µg/ml, préférentiellement de 0,5 à 2 µg/ml, le préférentiellement de 0,16 à 1,56 µg/ml d'aconitine.
  6. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon une ou plusieurs des revendications 1 À 2, la composition contenant entre 0,001 et 0,1 µg/ml, préférentiellement de 0,001 à 0,01 µg/ml, le préférentiellement de 0,003 à 0,006 µg/ml de cyanure de mercure.
  7. Composition pharmaceutique destinée à l'emploi dans un procédé pour le traitement d'une infection virale selon une ou plusieurs des revendications précédentes, la composition étant administrée à une dose journalière d'environ 20 µg/ml de sulfate d'atropine, 4 µg/ml d'aconitine et 0,016 µg/ml de cyanure de mercure.
EP14733198.7A 2013-06-28 2014-06-27 Composition pharmaceutique antivirale active Active EP3013343B1 (fr)

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EP14733198.7A EP3013343B1 (fr) 2013-06-28 2014-06-27 Composition pharmaceutique antivirale active

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EP13174235.5A EP2818167A1 (fr) 2013-06-28 2013-06-28 Composition pharmaceutique antivirale active
PCT/EP2014/063671 WO2014207187A1 (fr) 2013-06-28 2014-06-27 Composition pharmaceutique à action antivirale
EP14733198.7A EP3013343B1 (fr) 2013-06-28 2014-06-27 Composition pharmaceutique antivirale active

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EP (2) EP2818167A1 (fr)
JP (1) JP2016523874A (fr)
CN (1) CN105451738B (fr)
AU (1) AU2014301029A1 (fr)
BR (1) BR112015031585A2 (fr)
HK (1) HK1223038A1 (fr)
RU (1) RU2657575C2 (fr)
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CN111991392A (zh) * 2020-09-10 2020-11-27 青岛大学附属医院 一种抗疱疹病毒感染的生物碱及其组合物与应用
CN114931647B (zh) * 2022-05-20 2023-10-13 浙江瑞瞳生物科技有限公司 一种用于治疗i型单纯疱疹病毒感染的外用药物组合物及其用途
US20240316028A1 (en) * 2023-03-16 2024-09-26 Glaukos Corporation Ophthalmic cream formulations and their uses

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AU605781B2 (en) * 1986-08-07 1991-01-24 Medice Chem.-Pharm. Fabrik Putter Gmbh & Co. Kg N-alkylated quaternary nitrogen-containing fused heterocycles
US4867107A (en) 1988-02-03 1989-09-19 Sullivan Engine Works, Inc. Rotary vee engine
RU2143917C1 (ru) * 1999-05-21 2000-01-10 Общество с ограниченной ответственностью "Доктор Н" Гомеопатическое лекарственное средство для лечения гриппа и острых респираторных вирусных инфекций
US20020031509A1 (en) * 1999-12-28 2002-03-14 Bjorn Ortenheim Pharmaceutical composition and method for its manufacture
US8629283B2 (en) * 2008-03-06 2014-01-14 Icahn School Of Medicine At Mount Sinai Compounds that modulate negative-sense, single-stranded RNA virus replication and uses thereof

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Publication number Publication date
HK1223038A1 (zh) 2017-07-21
WO2014207187A1 (fr) 2014-12-31
RU2657575C2 (ru) 2018-06-14
JP2016523874A (ja) 2016-08-12
CN105451738B (zh) 2018-05-18
EP2818167A1 (fr) 2014-12-31
AU2014301029A1 (en) 2016-01-21
CN105451738A (zh) 2016-03-30
ZA201509091B (en) 2016-11-30
US9913861B2 (en) 2018-03-13
US20160143948A1 (en) 2016-05-26
RU2016101929A (ru) 2017-07-26
EP3013343A1 (fr) 2016-05-04
BR112015031585A2 (pt) 2017-07-25

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